Research performed at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has revealed that oxygen therapy aimed at helping mice with acute lung inflammation breathe paradoxically worsened their illness. The researchers say excess oxygen appears to thwart a natural process that limits lung tissue damage. They overcame this deleterious side effect, however, by adding an inhaled anti-inflammatory drug to the oxygen therapy.

"This research illustrates, in an animal model, a delicate balance between supplemental oxygen therapy and an innate tissue-preserving process that appears to operate best in low-oxygen conditions," says NIAID Director Anthony S. Fauci., M.D.

Michail Sitkovsky, Ph.D., senior author of the paper published this week in the journal PLoS Biology, believes the findings could have clinical implications. Supplemental oxygen is a life-saving therapy for patients with breathing problems, but it can harm the lungs if it is used for long periods. While the problem of oxygen-induced lung damage is well known, the biochemical processes leading to this damage have not been fully explained. Dr. Sitkovsky’s research reveals a possible mechanism behind this oxygen-induced damage and also provides evidence of a simple way to prevent it.

The current study extends research published in 2001 by Dr. Sitkovsky and colleagues into the role played by the molecule adenosine in regulating inflammation. Inflammatory chemicals produced by the immune system in response to infection or injury must eventually be switched off so that excessive tissue damage can be avoided. Dr. Sitkovsky and his colleagues have shown that inflammation leads to a drop in oxygen levels in the inflamed tissues. This, in turn, triggers the release of adenosine from surrounding cells. When adenosine binds to cell receptors in the inflamed region, it serves as a tissue-protecting stop signal, slowing the flood of damaging inflammatory molecules, the scientists found.

From these findings, they reasoned that oxygen therapy given to patients with acute lung inflammation might "short-circuit" this protective pathway by preventing oxygen levels from dropping enough to trigger the inflammation stop signal.

To explore this possibility in an animal model, Dr. Sitkovsky and his colleagues induced lung inflammation in three groups of mice. The first group of 15 mice did not receive any supplemental oxygen. While they sustained moderate lung damage, only two died. Another group of 15 mice with acute lung inflammation were treated with either 100 percent or 60 percent oxygen for 48 hours. These mice suffered very extensive lung damage, and 11 of 15 died. Finally, the scientists treated another 15 mice with acute lung inflammation with a combination of 100 percent oxygen and an adenosine-like drug to compensate for the oxygen-induced loss of natural adenosine. Only two mice in this group died, and exacerbation of lung inflammation by oxygen was prevented.

The investigators conclude that in this small animal model highly pure oxygen therapy without the addition of an adenosine substitute worsens pre-existing lung inflammation. "We suggest that these adenosine substitutes be evaluated for their possible usefulness in settings of acute lung inflammation due to infection or other causes, such as asthma or surgical trauma," says Dr. Sitkovsky.

Dr. Sitkovsky is now continuing his research at the newly established New England Inflammation and Tissue Protection Institute, a consortium at Northeastern University in Boston.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
References: A Ohta and M Sitkovsky. Role of adenosine receptors in down-regulation of inflammation and protection from tissue damage. Nature 414:916-20 (2001).